In recent years, microRNAs (miRs) have emerged as an important novel class of regulatory RNA, which have a profound impact on a wide array of biological processes. These small (typically 18-24 nucleotides long) non-coding RNA molecules can modulate protein expression patterns by promoting RNA degradation, inhibiting mRNA translation, and also affecting gene transcription. miRs play pivotal roles in diverse processes such as development and differentiation, control of cell proliferation, stress response and metabolism. The expression of many miRs was found to be altered in numerous types of human cancer, and in some cases strong evidence has been put forward in support of the conjecture that such alterations may play a causative role in tumor progression. The remarkable tissue-specificity of miR expression allows the development of novel approaches to molecular classification. There are currently about 1,100 known human miRs.
Renal cancers account for more than 3% of adult malignancies and cause more than 13,000 deaths per year in the US alone (Jemal, A., et al. 2008, Cancer statistics, CA Cancer J Clin 58, 71-96). The incidence of renal cancers in the US rose more than 50% between 1983 to 2002 and the estimated number of new cases per year rose from 39,000 estimated in 2006 to 54,000 estimated in 2008. Despite the trend of increased incidence of relatively small and kidney-confined disease, the rate of mortality has not changed significantly during the last 2 decades in the U.S. and Europe. In the 1980s, renal tumors were basically regarded as one disease: the higher the stage and the grade, the worse is the prognosis. After the 1980s, molecular biologists and pathologists described new entities with different morphological and biological characteristics. Evidence for different long-term prognosis for these subtypes makes the correct pathological diagnosis of a renal cancer critically important for the clinician. Currently, it is well accepted that renal cell carcinoma (RCC) is a family of carcinomas which arise from the epithelium of the renal tubules. The current classification of renal cell carcinoma includes four main types: Clear cell papillary, chromophobe, and collecting duct carcinoma, as well as unclassified renal cell carcinoma. Oncocytoma is a benign subtype of RCC.
Clear cell (conventional) renal carcinoma is the most frequent subtype of RCC and accounts for 60-70% of cases and account for the majority of renal cell cancer specific mortality. The term “conventional cell” is increasingly used to replace the name “clear cell”, because some types have eosinophilic cytoplasm, generating a more difficult diagnostic challenge. In tumors of clear cell, a characteristic vascular network is commonly observed. The clear cell (conventional) cell carcinoma type is associated with germ line and somatic mutations of the von Hippel-Lindau (VHL) suppressor gene and such mutations might impact the prognosis and might predict response to drugs targeting the VHL pathway. Papillary RCC typically consists of a central fibrovascular core with epithelial covered papillae. It is subclassified into type 1 and 2 tumors that differ in terms of morphology, genotype and clinical outcome. Genetically, this type of tumor is associated with polysomies of chromosomes 7 or 17 and deficiency of Y. Chromophobe RCC was first described in the mid 80ies and prior to that would have likely been classified as clear cell (conventional) RCC or as (benign) oncocytoma. The typical form exhibits balloon cells with an abundant granular pale cytoplasm, or eosinophilic cytoplasm that resemble the cells of oncocytoma. Such features as described above are characteristic of the histological subtypes, but inter-observer variations limit the accuracy of histological classification, with some types identified with a sensitivity of 70% or lower. Furthermore, underlying biological mechanisms playing important roles in these tumors are yet to be elucidated.
These different histological subtypes of RCC vary in their clinical courses and their prognosis, and different clinical strategies have been developed for their management. Patients with conventional cell renal carcinoma have a poorer prognosis, and differences may also exist between the prognosis of patients with papillary or chromophobe RCC. The histological types arise through different constellations of genetic alterations, and show expression or mutation in different oncogenic pathways; they therefore offer different molecular candidates for targeted therapy (e.g., mTOR, VEGF, KIT). Initial studies show differences in the responses of RCC subtypes to targeted therapies (Lopez-Beltran, A., et al. 2008, Semin Diagn Pathol 25, 232-44), and future therapies are likely to be individualized for the different types. The correct identification of these subtypes is therefore important choice of treatment, and for the selection of patients for clinical trials.
Based on the growing clinical demand for accurate diagnosis of RCC subtypes, recent studies focused on the immunohistochemical profiling of different carcinomas. Allory et al lately described a subset of 12 antibodies as base for classification of renal cell carcinomas. In this report AMACR, CK7 and CD10 had the most powerful classification trees with 78%-87% of carcinomas correctly classified (Allory, Y., et al. 2008, Histopathology 52, 158-66). Immunohistochemistry provides limited information for distinguishing chromophobe RCC from oncocytoma. However, the increasing number of smaller tumors and needle-biopsy procedures places a strain on immunohistochemical methods. In a recent large study of 235 cases, more than 20% of the core needle biopsies were nondiagnostic (Shannon, B. A., et al. 2008, J Urol 180, 1257-61). This emphasized the need for developing additional types of molecular markers for the classification of renal tumors and for their study.